P.C. Legacy: Miles From Montana, A Search for Hope

Far from the grass-covered prairie, the wild sage, and even the wheat waving in the wind, there is a glimmer of hope in the eyes and mind of a young woman from eastern Montana... miles and miles from home.

Miranda Orr grew up in Saco, Montana, the daughter of Jay and Carolyn Yeska, a country gal's life in a small town.

The inspiration for her interest in the medical field, namely in Alzheimer's research, was her grandmother, Vivian Siewing, also from Saco. Miranda and her family watched the disease take control of body, mind, spirit, and life. Vivian had graduated as valedictorian of her class and had always been fun-loving and active. To watch the change come over her as the disease grasped onto her was heart-wrenching.

Miranda was recently featured in the January 2023 National Geographic magazine for her research on Alzheimer's disease. She currently works at the Wake Forest University School of Medicine in Winston-Salem, N.C.

In a special on the topic, featured on KRTV, a Great Falls news program recently, it stated that the McLaughlin Research Institute for Biomedical Sciences in Great Falls has served a major role in biomedical research in Montana for nearly 70 years. McLaughlin Research Institute says, "The need for clinical research expansion in the state of Montana has become more important than ever. They noted that Montana has consistently ranked in the bottom 10% when it comes to participation and representation in clinical research nationwide. Montana has the sixth oldest population ratio in the nation. A little over 19 percent of our total population is over the age of 65."

Miranda received her Ph. D. from Montana State University in Neuroscience and followed up with research at the McLaughlin Research Institute in Great Falls. That research was focused on Alzheimer's disease, and looking at how we can study Alzheimer's disease in mice.

From there, she went to San Antonio for her post-doctorate fellowship, studying at the Barshop Institute for Longevity and Aging; it is one of the premier institutes that focuses on how we age – how all organisms age.

"That was really a major shift in my research, because as we grow older we have an increased risk of developing all sorts of diseases, and the disease I am focused on studying is Alzheimer's disease. The greatest risk factor for developing Alzheimer's disease is advanced age."

Miranda continued, "So when I heard the first lecture at the Barshop Institute, from this professor that was describing a fundamental process that happens to cells, how he was describing it sounded exactly what I was finding in Alzheimer's. So at that point, I made a link between aging and how cells become dysfunctional in Alzheimer's disease, and that process is called cellular senescence. It is a complex process where cells that become stressed don't die and they don't divide, and if they die and are not replaced that can be bad for a tissue, and cells that are damaged do divide that can lead to cancer – so that is also bad."

She said a third option is a senescence. "They don't die, and they actually can't die, so they are damaged and they stay alive. When they stay they end up damaging healthy cells around them. Because of this, they are often referred to as "toxic zombie cells" because they have transformed into a poorly functioning and actually very dysfunctional and harmful neighbor that kills surrounding cells."

From that point, her research has focused on trying to understand that in Alzheimer's disease. "In some of our early days, we had identified these cells in the brains of people who had passed away and then we used mice – the same mice I used in my Ph. D. in Montana, to see if they also developed the senescence cells, and they did. So the next study was to use drugs that targeted the senescence cells for their clearance and when we treated the mice with the drug that killed the toxic cell we saw an improvement; compared to the mice that received a placebo treatment (similar to a sugar pill in a clinical trial), the mice that received the drug, their brains were much better. The structure was better, the function was better, and what we interpreted from this study was that from the point in when we treated the mice with the drug, the disease did not continue to get worse."

"That's really important because the age we started the treatment was similar to a 70-year-old-person with advanced stages of Alzheimer's disease. The goal of our study was to know whether or not if we did move this treatment to people today, that had advanced Alzheimer's disease today, might it help them, and the answer was yes."

"From that, they applied for funding to initiate a phase 2 clinical trial. The Alzheimer's Drug Discovery Foundation is now supporting this trial – so they are enrolling people with early-stage Alzheimer's disease. Half of the people that get enrolled will get the drug and half of the people enrolled will get the placebo (sugar pill). No one knows who will be getting the drug and no one will know who is getting the placebo.

They are recruiting participants at Wake Forest as well as San Antonio."

In an effort to increase the inclusion and expansion of clinical research in Montana, McLaughlin Research Institute has launched a registry of potential participants for clinical research. This registry is open to any adults of any age or diagnosis. The purpose is to gain a list of potential participants for future research studies. The registry is referred to as "HERO" (Helping Expand Research Opportunities).

To learn more, contact McLaughlin Research Institute for Biomedical Science at 406-452-6208.